HIV associated salivary gland disease (HIVSGD) also known as benign lymphoepithelial lesion (BLL) is an AIDS defining pediatric disease with up to 40% of children affected. BLL prevalence is increasing in the adult population even after widespread use of highly active antiretroviral therapy and is detected in up to 48% of adults in the developing world. This disfiguring, often stigmatizing, disease drastically impacts quality of life (QOL). BLL precedes development of cancer in the affected gland in a significant portion of affected individuals and predisposes to rampant caries and progressive periodontal disease. The potential etiologic agent has not been identified hence, there are not effective therapies. The theme of this proposal to define the association between the tumor-inducing polyomavirus BK (BKV) and development/exacerbation of BLL. As such, 1) molecular epidemiologic studies should support this association and 2) BKV titers should correlate with disease severity. Towards achieving our goals, our preliminary studies have identified the human polyomavirus, BK in BLL 1) BK viral gene products were consistently detected in BLL, 2) individuals were viremic, and 3) BKV was shed at elevated levels in their oral secretions. We have developed the first in vitro BKV salivary gland cell infection system of productive non-lytic infection, mirroring the disease, and enabling mechanistic analyses of BK infection. Using BKV targeted antiviral drugs, we can inhibit replication of BKV in our in vitro model. Infection of rodents with homologous polyomaviruses cause similar salivary gland disease in these animals. Taken together these findings led to development of the following specific aims that will probe the role of BKV in salivary gland pathology and will define the association between BKV permissive salivary gland infection and BLL. Following molecular guidelines for causation, these aims will be achieved by AIM 1) To conduct a prospective case control study of BLL where BKV determinants of replication, anti-BKV antibody status, and viral gene expression will be analyzed in gland, and body fluids (saliva, sera, urine, plasma, PBL for study of viral compartmentalization). We will correlate salivary function (resting and stimulated flow) and salivary protein secretion in BLL with BKV titers. A pilot randomized control trial will be performed within the BLL group. The BLL group will be randomized to BKV targeted antiviral or placebo AIM 2) To determine if BLL is a manifestation of primary infection in children in a retrospective longitudinal study. HIV+BLL+ children with the disease and matched exposed uninfected controls will be assessed. AIM 3) To determine if BLL in adults is the result of a reactivation event stimulated by HAART initiation in retrospective longitudinal study. The proposed molecular epidemiologic studies explore the potential for BKV generated salivary gland cellular lesions that affect processes critical to normal glandular function and may lend support for causal association between BKV and BLL. Our expertise in oral viral pathogenesis and clinical trials will facilitate this important effort.